Reversal of cardiac hypertrophy and fibrosis from pressure overload by tetrahydrobiopterin - Efficacy of recoupling nitric oxide synthase as a therapeutic strategy
Reversal of cardiac hypertrophy and fibrosis from pressure overload by tetrahydrobiopterin - Efficacy of recoupling nitric oxide synthase as a therapeutic strategy
复制标题
DOI：
10.1161/circulationaha.107.737031
复制
发表时间：
2008-05-20
期刊：
影响因子：
37.8
通讯作者：
Kass, David A.
中科院分区：
文献类型：
--
作者：
Moens, An L.;Takimoto, Eiki;Kass, David A.
背景-持续压力超负荷诱导病理性心脏肥大和功能障碍。与一氧化氮合酶（NOS）解偶联相关的氧化应激可能起重要作用。我们测试了四氢生物蝶呤（BH 4）是否可以recouple NOS和扭转预先建立的先进的肥大，纤维化，和dysfunctions.Methods和Results-C57/B16小鼠进行横向主动脉缩窄4周，增加心脏质量（190%）和舒张期尺寸（144%），降低射血分数（-46%），并触发NOS解偶联和氧化应激。然后口服BH 4，持续5周以上的压力超负荷。在不降低负荷的情况下，BH 4逆转了肥大和纤维化，重新偶联了内皮NOS，降低了氧化应激，改善了心室和心肌细胞功能，而未经治疗的心脏则恶化了。如果BH 4开始在压力超负荷的发病，它没有抑制肥大超过第一周时，NOS活性仍然保留，即使在未经处理的横向主动脉缩窄心脏。然而，当NOS活性下降时，BH 4停止了随后的重塑。一种广泛的抗氧化剂，Tempol，也减少了氧化应激，但没有重新耦合NOS或逆转持续的横向主动脉收缩恶化的肥大/纤维化。微阵列分析显示两种治疗方法的基因表达谱非常不同。BH 4不增强净蛋白激酶G活性。最后，转基因小鼠增强BH 4合成局限于内皮细胞对压力超负荷保护，表明外源性BH 4靶向心肌细胞和fibroblast.Conclusions-NOS recoupling外源性BH 4改善预先存在的先进的心脏肥大/纤维化，是更有效的比一个不太有针对性的抗氧化剂的方法（Tempol）。这些数据强调了心肌细胞NOS解偶联在肥厚性心脏病中的重要性，并支持BH 4作为治疗这种疾病的潜在新方法。
Background-Sustained pressure overload induces pathological cardiac hypertrophy and dysfunction. Oxidative stress linked to nitric oxide synthase (NOS) uncoupling may play an important role. We tested whether tetrahydrobiopterin (BH4) can recouple NOS and reverse preestablished advanced hypertrophy, fibrosis, and dysfunction.Methods and Results-C57/Bl6 mice underwent transverse aortic constriction for 4 weeks, increasing cardiac mass (190%) and diastolic dimension (144%), lowering ejection fraction (-46%), and triggering NOS uncoupling and oxidative stress. Oral BH4 was then administered for 5 more weeks of pressure overload. Without reducing loading, BH4 reversed hypertrophy and fibrosis, recoupled endothelial NOS, lowered oxidant stress, and improved chamber and myocyte function, whereas untreated hearts worsened. If BH4 was started at the onset of pressure overload, it did not suppress hypertrophy over the first week when NOS activity remained preserved even in untreated transverse aortic constriction hearts. However, BH4 stopped subsequent remodeling when NOS activity was otherwise declining. A broad antioxidant, Tempol, also reduced oxidant stress yet did not recouple NOS or reverse worsened hypertrophy/fibrosis from sustained transverse aortic constriction. Microarray analysis revealed very different gene expression profiles for both treatments. BH4 did not enhance net protein kinase G activity. Finally, transgenic mice with enhanced BH4 synthesis confined to endothelial cells were unprotected against pressure overload, indicating that exogenous BH4 targeted myocytes and fibroblasts.Conclusions-NOS recoupling by exogenous BH4 ameliorates preexisting advanced cardiac hypertrophy/fibrosis and is more effective than a less targeted antioxidant approach (Tempol). These data highlight the importance of myocyte NOS uncoupling in hypertrophic heart disease and support BH4 as a potential new approach to treat this disorder.